Blocking NAD(+)/CD38/cADPR/Ca(2+) pathway in sepsis prevents organ damage.

Abstract

BACKGROUND:

Although the nicotinamide adenine dinucleotide (NAD(+))/CD38/cyclic ADP ribose (cADPR)/Ca(2+) signaling pathway has been shown to regulate intracellular calcium homeostasis and functions in multiple inflammatory processes, its role in sepsis remains unknown. The aim of this study was to determine whether the NAD(+)/CD38/cADPR/Ca(2+) signaling pathway is activated during sepsis and whether an inhibitor of this pathway, 8-Br-cADPR, protects the organs from sepsis-induced damage.

MATERIALS AND METHODS:

Male Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP) or sham laparotomies. NAD(+), cADPR, CD38, and intracellular Ca(2+) levels were measured in the hearts, livers, and kidneys of septic rats at 0, 6, 12, 24, and 48 h after CLP surgery. Rats were also divided into sham, CLP, and CLP+8-Br-cADPR groups, and the hearts, livers, and kidneys were hematoxylin-eosin-stained and assayed for malondialdehyde and superoxide dismutase activities.

RESULTS:

NAD(+), cADPR, CD38, and intracellular Ca(2+) levels increased in the hearts, livers, and kidneys of septic rats as early as 6-24 h after CLP surgery. Treatment with 8-Br-cADPR inhibited sepsis-induced intracellular Ca(2+) mobilization, attenuated tissue injury, reduced malondialdehyde levels, and increased superoxide dismutase activity in septic rats.

CONCLUSIONS:

The NAD(+)/CD38/cADPR/Ca(2+) signaling pathway was activated during sepsis in the CLP rat model. Blocking this pathway with 8-Br-cADPR protected hearts, livers, and kidneys from sepsis-induced damage.

• Authors: Qian-Yi Peng, Mei-Lin Ai, Li-Na Zhang, Yu Zou, Xin-Hua Ma, Yu-Hang Ai
• Journal: The Journal of surgical research (J Surg Res) Vol. 201 Issue 2 Pg. 480-9 (Apr 2016) ISSN: 1095-8673 [Electronic] United States
• PMID: 27020835 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• 8-bromo-cyclic-ADP-ribose
• Membrane Glycoproteins
• NAD
• Cyclic ADP-Ribose
• Malondialdehyde
• Superoxide Dismutase
• ADP-ribosyl Cyclase
• Cd38 protein, rat
• ADP-ribosyl Cyclase 1
• Calcium

Topics

• ADP-ribosyl Cyclase (metabolism)
• ADP-ribosyl Cyclase 1 (metabolism)
• Animals
• Calcium (metabolism)
• Calcium Signaling (drug effects)
• Cyclic ADP-Ribose (analogs & derivatives, metabolism, pharmacology, therapeutic use)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Male
• Malondialdehyde (metabolism)
• Membrane Glycoproteins (metabolism)
• Multiple Organ Failure (etiology, prevention & control)
• NAD (metabolism)
• Random Allocation
• Rats, Sprague-Dawley
• Sepsis (complications, metabolism)
• Superoxide Dismutase (metabolism)